Evidence accumulated over the past decade has strengthened the case for T cell-mediated mechanisms of protection against HIV. A major impediment to the development of an HIV-1 vaccine that elicits such immunity, however, has been the lack of a T cell-mediate response that correlates with protection. For example, there is no definitive evidence correlating CTL responses with protection against SIV or HIV. On the other hand, recent evidence showing that chemokine-secreting T cells can suppress HIV-1 infection in vitro suggest a new mechanism of T cells can suppress HIV-1 infection in vitro, suggests a new mechanism of T cell-mediated protection. Clearly, these studies justify continued investigation of the means by which T cell-mediated responses can be induced by HIV-1 vaccines. In this vein, the central hypothesis of this proposal is that a live oral Salmonella-SIV vaccine vector will induce such responses in mice and non human primates. In the preliminary data section we present immunological data that strengthen our central hypothesis. Thus, we showed that a single oral dose of a Salmonella-HIV vector, bearing a secreted form of glycosylated gp120, induced gp120-specific T cells that were predominated by IFN-gamma- secreting CD4+ T cells and a strong gp120-specific mucosal response. Furthermore, our data suggest that gp120-specific beta chemokine-secreting responses develop in the mucosal compartment after oral immunization with a Salmonella-HIV vaccine vector. Finally, we have shown that human- specific attenuated Salmonella strain CVD 908 is well tolerated and immunogenic in volunteers. We now propose to extent these finding by constructing Salmonella vectors that express chimeric SIV/MAC/239 Gag-Nef fusions and to characterize the immunogenicity of these constructs for SIV-specific T cell responses in mice. Further, the Salmonella-SIV construct that elicits the strongest SIV-specific T cell responses in mice will be evaluated in an immunogenicity and challenge trial in non-human primates. We believe that this approach will provide fundamental information germane to the development of an oral Salmonella-HIV-1 vaccine.